Attachment of Leishmania promastigotes to the midgut lining of the sand fly is crucial to the successful completion of their life cycle in the fly, serving to prevent excretion of developing promastigotes along with the bloodmeal remnants. Lipophosphoglycan (LPG), the major glycoconjugate on the surface of Leishmania promastigotes, has been implicated as the ligand-mediating midgut attachment. The involvement of LPG side-chain sugars in the species-specific attachment of Leishmania parasites to their vectors has been most clearly demonstrated for L. major and P. papatasi, for which side-chains terminating in beta-galactose residues are required. The nature of the LPG receptor in sand flies has remained largely undefined. PpGalec, a cDNA encoding a novel tandem repeat galectin, was identified by high-throughput screening of a midgut library of Phlebotomus papatasi. Expression of PpGalec in P. papatasi is strongly upregulated in adult females and is restricted to midgut tissue. The binding specificity of rPpGalec is restricted to Leishmania promastigotes bearing poly-Gal (b1-3) side chains on their LPG. PpGalec is distributed throughout the abdominal and thoracic midgut and localized on the luminal surface of midgut cells. Most importantly, antibodies against PpGalec inhibited in vitro midgut binding of L. major PG and parasites and severely impaired parasite development and survival in the insect midgut. The use of RNA interference in silencing the expression of PpGal is being developed. Other genes targeted for silencing by RNAi include those encoding chymoptrypsin (PpChym2), involved in bloodmeal digestion, and chitinase, responsible for the breakdown of the peritrophic membrane. The first analysis of the regulation of genes encoding the main enzymes involved in bloodmeal digestion, including trypsin, chymotrypsin, and chitinase, is being completed.